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DOI: 10.1055/s-0028-1082325
© Georg Thieme Verlag KG Stuttgart · New York
The Role of IGF-system in Vascular Insulin Resistance
Publication History
received 02.10.2007
accepted 23.01.2008
Publication Date:
15 September 2008 (online)
![](https://www.thieme-connect.de/media/hmr/200809/lookinside/thumbnails/10.1055-s-0028-1082325-1.jpg)
Abstract
Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (≥10−8 M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10−9–10−10 M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/IGF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-I hybrid receptors.
Key words
endothelial cells - vascular smooth muscle - insulin - IGF-1 receptors
References
- 1 Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978; 253 2769-2776
- 2 Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985; 313 756-761
- 3 Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le-Bon T, Kathuria S, Chen E. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 1986; 5 2503-2512
- 4 Moxham CP, Duronio V, Jacobs S. Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. J Biol Chem. 1989; 264 13238-13244
- 5 Soos MA, Siddle K. Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors. Biochem J. 1989; 263 553-563
- 6 Möller C, Arner P, Sonnenfeld T, Norstedt G. Quantitative comparison of insulin-like growth factor mRNA levels in human and rat tissues analysed by a solution hybridization assay. J Mol Endocrinol. 1991; 7 213-222
- 7 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab. 1994; 79 872-878
- 8 Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16 3-34
- 9 Frystyk J. Free insulin-like growth factors measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res. 2004; 14 337-375
- 10 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity?. Growth Horm IGF Res. 2002; 12 84-90
- 11 Bar RS, Hoak JC, Peacock ML. Insulin receptors in human endothelial cells: identification and characterization. J Clin Endocrinol Metab. 1978; 47 699-702
- 12 King GL, Buzney SM, Kahn CR, Hetu N, Buchwald S, Macdonald SG, Rand LI. Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels. J Clin Invest. 1983; 71 974-979
- 13 Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin, direct measurement in vascular endothelial cells. J Clin Invest. 1996; 98 894-898
- 14 Dekker Nitert M, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ. IGF-I/Insulin Hybrid Receptors in Human Endothelial Cells. Mol Cell Endocrinol. 2005; 229 31-37
- 15 Aljada A, Ghanim H, Assian E, Dandona P. Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. Metabolism. 2002; 51 487-491
- 16 Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P, Spagnoli LG, Sesti G, Lauro R. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation. 2002; 106 466-472
- 17 Salt IP, Morrow VA, Brandie FM, Connell JM, Petrie JR. High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells. J Biol Chem. 2003; 278 18791-18797
- 18 Chisalita SI, Dekker-Nitert M, Arnqvist HJ. Characterisation of receptors for insulin-like growth factor-I and insulin in human coronary artery endothelial cells. Growth Horm IGF Res. 2006; 16 258-266
- 19 Chisalita SI, Arnqvist HJ. Insulin-like growth factor-I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol. 2004; 286 E896-E901
- 20 Banskota NK, Taub R, Zellner K, Olsen P, King GL. Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. Diabetes. 1989; 38 123-129
- 21 Arnqvist HJ, Bornfeldt KE, Chen Y, Lindström T. The IGF-system in vascular smooth muscle; Interaction with insulin and growth factors. Metabolism. 1995; 44 ((Suppl 4)) 58-66
- 22 Avena R, Mitchell ME, Carmody B, Arora S, Neville RF, Sidaway AN. Insulin-like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors. Am J Surg. 1999; 178 156-161
- 23 Ward CW, Lawrence MC, Streltsov VA, Adams TE, MacKern NM. The insulin and EGF receptor structures: new insights into ligand-induced receptor activation. Trends Biochem Sci. 2007; 32 129-137
- 24 Dupont J, Dunn SE, Barrett JC, LeRoith D. Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression. Recent Prog Horm Res. 2003; 58 325-342
- 25 Andreozzi F, Laratta E, Procopio C, Hribal ML, Sciacqua A, Perticone M, Miele C, Perticone F, Sesti G. Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. Mol Cell Biol. 2007; 27 2372-2383
- 26 Konopatskaya O, Shore AC, Tooke JE, Whatmore J. A role for heterotrimeric GTP-binding proteins and ERK1/2 in insulin-mediated, nitric-oxide-dependent, cyclic GMP production in human umbilical vein endothelial cells. Diabetologia. 2005; 48 595-604
- 27 Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int. 1994; 45 598-604
- 28 Staiger K, Staiger H, Schweitzer MA, Metzinger E, Balletshofer B, Häring HU, Kellerer M. Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells. Diabetologia. 2005; 48 1898-1905
- 29 Artwohl M, Brunmair B, Furnsinn C, Holzenbein T, Rainer G, Freudenthaler A, Porod EM, Huttary N, Baumgartner-Parzer SM. Insulin does not regulate glucose transport and metabolism in human endothelium. Eur J Clin Invest. 2007; 37 643-650
- 30 Mann GE, Yudilevich DL, Sobrevia L. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev. 2003; 83 183-252
- 31 Giannini S, Cresci B, Pala L, Ciucci A, Franchini A, Manuelli C, Fujita-Yamaguchi Y, Cappugi P, Zonefrati R, Rotella CM. IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells. J Endocrinol. 2001; 171 273-284
- 32 Chisalita SI, Arnqvist HJ. Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells. Diabetologia. 2005; 48 2155-2161
- 33 Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, Bennett MR. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res. 2001; 88 895-902
- 34 Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995; 30 825-834
- 35 Johansson GS, Arnqvist HJ. Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells. Am J Physiol Endocrinol Metab. 2006; 291 E1124-E1130
- 36 Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J. 1993; 290 419-426
- 37 Meyts P De, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov. 2002; 1 769-783
- 38 Moller DE, Yokota A, Caro JF, Flier JS. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. Mol Endocrinol. 1989; 3 1263-1269
- 39 Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, MacClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990; 9 2409-2413
- 40 Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999; 19 3278-3288
- 41 Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002; 277 39684-39695
- 42 Slaaby R, Schäffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006; 281 25869-25874
- 43 Benyoucef S, Surinya KH, Hadaschik D, Siddle K. Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation. Biochem J. 2007; 403 603-613
- 44 Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, Siddle K, Goldfine ID, Belfiore A. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res. 1999; 5 1935-1944
- 45 Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987; 80 1-6
- 46 Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990; 85 1844-1852
- 47 Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994; 94 1172-1179
- 48 Serné EH, IJzerman RG, Gans RO, Nijveldt R, Vries G De, Evertz R, Donker AJ, Stehouwer CD. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes. 2002; 51 1515-1522
- 49 Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005; 25 989-994
- 50 Pendergrass M, Fazioni E, Collins D, DeFronzo RA. IGF-I increases forearm blood flow without increasing forearm glucose uptake. Am J Physiol. 1998; 275 E345-E350
- 51 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116 1793-1801
- 52 Wei Y, Chen K, Whaley-Connell AT, Stump CS, Ibdah JA, Sowers JR. Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species. Am J Physiol Regul Integr Comp Physiol. 2008; 294 R673-R680
- 53 Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999; 104 447-457
- 54 Gosmanov AR, Stentz FB, Kitabchi AE. De novo emergence of insulin-stimulated glucose uptake in human aortic endothelial cells incub-ated with high glucose. Am J Physiol Endocrinol Metab. 2006; 290 E516-E522
- 55 Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007; 1 46-56
- 56 Cusi K, DeFronzo R. Recombinant human insulin-like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance. J Clin Endocrinol Metab. 2000; 85 3077-3084
- 57 Froesch ER, Ze D, Hussain MP. Metabolic and therapeutic effects of insulin-like growth factor I. Horm Res. 1994; 42 66-71
- 58 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, Tauber M, Bastide R, Rosenfeld R, Tauber JP. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab. 1996; 22 245-250
Correspondence
H. J. ArnqvistMD, PhD
Department of Clinical and Experimental Medicine
Division of Cell Biology
University Hospital
581 85 Linköping
Sweden
Phone: +46/13/22 27 89
Fax: +46/13/22 42 73
Email: hans.arnqvist@ibk.liu.se